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Timothy Tellinghuisen, Ph.D.

Associate Professor
Department of Infectious Diseases
Florida Campus
tellint@scripps.edu
(561) 228-3458

Scripps Research Joint Appointments

Department of Immunology and Microbial Science
Faculty, Graduate Program

Other Joint Appointments

Adjunct Assistant Professor, Department of Chemistry & Biochemistry, Florida Atlantic University

Research Focus

Hepatitis C virus (HCV) infection is a significant public health crisis, with more than 3% of the world’s population persistently infected. Long-term virus replication in the liver of these individuals results in progressive disease including hepatitis, cirrhosis, and ultimately, liver failure. Although the therapeutics for treating HCV have greatly improved in the last half decade, more work will be needed to enact the global eradication of this insidious pathogen, and understanding the mechanisms by which this simple virus maintains persistent infections is of paramount importance to this effort. Unlike many other viruses that can establish long term infections, HCV doesn’t integrate into the host DNA, form episomal elements in the nucleus, or remain quiescent; Persistent HCV infections are maintained only through active virus replication. This phenomenon requires HCV to avoid innate and acquired immunity, promote survival of the infected cell, and tightly control the rate of RNA replication and virion production such that infections never exhaust the available pool of hepatocytes.  Much of this regulation occurs at a cellular level and can be studied with recent advances in HCV infectious virus culture systems. We have begun investigating host factors and pathways manipulated during HCV to promote hepatocyte survival and promote viral persistence using a variety of high throughput genetic screening tools. One of these factors, CARD14, is essential for efficient HCV RNA replication, and appears to promote pro-survival gene expression during infection. We are also looking at the delicate balance of HCV infections at the level of RNA replication, and the interface of this lifecycle phase with later assembly events, by studying viral and host proteins, and their modifications, that are required for replication and assembly. We have begun to decipher how HCV RNA is directed out of replication and to virion assembly, both in terms of changes to viral protein modifications and localization, and in terms of alterations in the spectrum of host factors with which they interact. This work primarily focuses on the NS5A and NS2 proteins, as they are most closely associated with the replication-assembly nexus, although all HCV proteins and their cellular partner are of interest.  The ultimate goal of our work is to identify and uncouple the balance HCV infection creates, with an aim at short circuiting stable infections, and perhaps eliminating viral persistence.

Education

B.S., Biology, University of Massachusetts Lowell, 1992
M.S., Biology, University of Massachusetts Lowell, 1994
Ph.D., Biology, Purdue University, 2000

Selected References

Tellinghuisen, T.L., Marcotrigiano, J., Gorbalenya, A.E. and Rice, C.M. The Hepatitis C Virus NS5A Protein is a Zinc Metalloprotein. J. Biol. Chem. 279,47:48576-87, 2004.

Tellinghuisen, T.L., Marcotrigiano, J. and Rice, C.M. Structure of the Zinc-Binding Domain of an Essential Component of the Hepatitis C Virus Replicase. Nature. 435: 374-79, 2005.

Lindenbach, B.D., Evans, M.J., Syder, A., Woelk, B., McKeating, J.A., Tellinghuisen, T.L. and Rice, C.M. Complete Replication of Hepatitis C Virus in Cell Culture. Science. 309: 623-26, 2005.

Tellinghuisen, T.L., Foss, K.L., and Treadaway, J. C., Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLOS Pathogens. Mar 21;4(3), 2008.

Brimacombe, C.L, Grove, J., Meredith, L.W., Syder, A.J., Flores, M.V., Timpe, J., Krieger, S.E., Baumert, T.F., Tellinghuisen, T.L., Wong-Staal, F., Balfe, P., and McKeating, J.A. Neutralizing antibody resistant cell to cell hepatitis C transmission. J.Virology. Jan;85(1):596-605, 2011.

LeMay, K.L., Treadaway, J., Angulo-Herrera, I., and Tellinghuisen, T.L., A Hepatitis C Virus NS5A Phosphorylation Site that Regulates RNA ReplicationJ Virology. Jan;87(2):1255-60, 2013.